UHRF1 downmodulation enhances antitumor effects of histone deacetylase inhibitors in retinoblastoma by augmenting oxidative stress‐mediated apoptosis

Kim, Jong Kyong; Kan, Guangyan; Mao, Yu; Wu, Zhixuan; Tan, Xionghong; He, Heng; Lee, Chunsik

doi:10.1002/1878-0261.12607

Cited by 28 publications

(34 citation statements)

References 38 publications

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“…[224] Depletion of ubiquitin-like with PHD and RING finger domains 1 reduces TRX2 and increases intracellular ROS in retinoblastoma cells. [225] Glioma nitric oxide synthase 2 induces the S-nitrosylation of TRX2 and mitochondrial caspase 3 in microglial cells, reducing their activity and promoting tumorigenesis.…”

Section: Trx1/2mentioning

confidence: 99%

The NRF2, Thioredoxin, and Glutathione System in Tumorigenesis and Anticancer Therapies

et al. 2020

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Cancer remains an elusive, highly complex disease and a global burden. Constant change by acquired mutations and metabolic reprogramming contribute to the high inter- and intratumor heterogeneity of malignant cells, their selective growth advantage, and their resistance to anticancer therapies. In the modern era of integrative biomedicine, realizing that a personalized approach could benefit therapy treatments and patients’ prognosis, we should focus on cancer-driving advantageous modifications. Namely, reactive oxygen species (ROS), known to act as regulators of cellular metabolism and growth, exhibit both negative and positive activities, as do antioxidants with potential anticancer effects. Such complexity of oxidative homeostasis is sometimes overseen in the case of studies evaluating the effects of potential anticancer antioxidants. While cancer cells often produce more ROS due to their increased growth-favoring demands, numerous conventional anticancer therapies exploit this feature to ensure selective cancer cell death triggered by excessive ROS levels, also causing serious side effects. The activation of the cellular NRF2 (nuclear factor erythroid 2 like 2) pathway and induction of cytoprotective genes accompanies an increase in ROS levels. A plethora of specific targets, including those involved in thioredoxin (TRX) and glutathione (GSH) systems, are activated by NRF2. In this paper, we briefly review preclinical research findings on the interrelated roles of the NRF2 pathway and TRX and GSH systems, with focus given to clinical findings and their relevance in carcinogenesis and anticancer treatments.

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Section: Trx1/2mentioning

confidence: 99%

The NRF2, Thioredoxin, and Glutathione System in Tumorigenesis and Anticancer Therapies

et al. 2020

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“…Of note, UHRF1 protein expression is much higher in primary MM tumor and MM cells compared to normal hPBMCs, and with an unfavorable prognosis in MM. Knockdown of UHRF1 expression in cancer cells significantly suppressed cell growth, indicating that UHRF1 is essential for the progression of cancer [39]. Interestingly, normal cells (BaF 3 and normal hPBMCs) expressing low UHRF1 are insensitive to BBR in contrast to MM cells which supports that UHRF1 may be the target of BBR.…”

Section: Discussionmentioning

confidence: 87%

Identification of berberine as a novel drug for the treatment of multiple myeloma via targeting UHRF1

Yin

Nie

et al. 2020

BMC Biol

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Background: Current therapies for multiple myeloma (MM) are associated with toxicity and resistance, highlighting the need for novel effective therapeutics. Berberine (BBR), a botanical alkaloid derived from several Berberis medicinal plants, has exhibited anti-tumor effects, including against multiple myeloma (MM); however, the molecular mechanism underlying the anti-MM effect has not been previously described. This study aimed to identify the target of berberine and related mechanisms involved in its therapeutic activity against MM. Results: Here, we demonstrated that BBR treatment killed MM cells in vitro and prolonged the survival of mice bearing MM xenografts in vivo. A screening approach integrating surface plasmon resonance (SPR) with liquid chromatography-tandem mass spectrometry (LC-MS/MS) identified UHRF1 (ubiquitin-like with PHD and RING Finger domains 1) as a potential target of BBR. Combining molecular docking and SPR analysis, we confirmed UHRF1 as a BBR-binding protein and discovered that BBR binds UHRF1 in the tandem tudor domain and plant homeodomain (TTD-PHD domain). BBR treatment induced UHRF1 degradation via the ubiquitin-dependent proteasome system and reactivated p16 INK4A and p73 in MM cells. Overexpression of UHRF1 promoted the MM cell proliferation and rendered MM cells more resistant to BBR, while silencing of UHRF1 with siRNA attenuated BBR-induced cytotoxicity. Conclusions: In summary, our study has identified UHRF1 as a direct target of BBR and uncovered molecular mechanisms involved in the anti-MM activity of BBR. Targeting UHRF1 through BBR may be a novel therapeutic strategy against MM.

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“…Another study showed increase in ROCKII protein level in NMDA-induced retinal neurotoxicity, and its inhibitor acted as neuroprotective agent by abolishing the increase in ROCKII level ( Kitaoka et al, 2004 ). Apart from this, UHRF1 , which encode a protein that regulates DNA and histone methylation, and NR1H4 (Nuclear Receptor Subfamily 1 Group H Member 4), which encode ligand-activated transcription factor, are also found to be linked with inflammation ( Fiorucci et al, 2010 ; Wang et al, 2018 ), oxidative stress ( Gai et al, 2017 ; J. K. Kim J. K. et al, 2020 ), and angiogenesis ( Guo and Mo, 2020 ). Interestingly, in the present study, NR1H4 was also found to be one of the targets of down-regulated miRNA identified in a plasma sample of NPDR cases and thus can act as a preferred candidate in studies concerned with identification of circulatory prognostic biomarker for DR.…”

Section: Discussionmentioning

confidence: 99%

Integrative Computational Approach Revealed Crucial Genes Associated With Different Stages of Diabetic Retinopathy

et al. 2020

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The increased incidence of diabetic retinopathy (DR) and the legacy effect associated with it has raised a great concern toward the need to find early diagnostic and treatment strategies. Identifying alterations in genes and microRNAs (miRNAs) is one of the most critical steps toward understanding the mechanisms by which a disease progresses, and this can be further used in finding potential diagnostic and prognostic biomarkers and treatment methods. We selected different datasets to identify altered genes and miRNAs. The integrative analysis was employed to find potential candidate genes (differentially expressed and aberrantly methylated genes that are also the target of altered miRNAs) and early genes (genes showing altered expression and methylation pattern during early stage of DR) for DR. We constructed a protein-protein interaction (PPI) network to find hub genes (potential candidate genes showing a greater number of interactions) and modules. Gene ontologies and pathways associated with the identified genes were analyzed to determine their role in DR progression. A total of 271 upregulated-hypomethylated genes, 84 downregulated-hypermethylated genes, 11 upregulated miRNA, and 30 downregulated miRNA specific to DR were identified. 40 potential candidate genes and 9 early genes were also identified. PPI network analysis revealed 7 hub genes (number of interactions >5) and 1 module (score = 5.67). Gene ontology and pathway analysis predicted enrichment of genes in oxidoreductase activity, binding to extracellular matrix, immune responses, leukocyte migration, cell adhesion, PI3K-Akt signaling pathway, ECM receptor interaction, etc., and thus their association with DR pathogenesis. In conclusion, we identified 7 hub genes and 9 early genes that could act as a potential prognostic, diagnostic, or therapeutic target for DR, and a few early genes could also play a role in metabolic memory phenomena.

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UHRF1 downmodulation enhances antitumor effects of histone deacetylase inhibitors in retinoblastoma by augmenting oxidative stress‐mediated apoptosis

Abstract: hydroxamic acid; TXN2, thioredoxin-2; UHRF1, ubiquitin-like with PHD and RING finger domains 1.

Cited by 28 publications

References 38 publications

The NRF2, Thioredoxin, and Glutathione System in Tumorigenesis and Anticancer Therapies

The NRF2, Thioredoxin, and Glutathione System in Tumorigenesis and Anticancer Therapies

Identification of berberine as a novel drug for the treatment of multiple myeloma via targeting UHRF1

Integrative Computational Approach Revealed Crucial Genes Associated With Different Stages of Diabetic Retinopathy

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